Osmotic delivery system having space-efficient piston

ABSTRACT

An osmotic delivery system having a space-efficient piston is provided. The enclosure has an interior holding the piston, a protein or peptide, and an osmotic agent. The piston is movable with respect to an interior surface of the capsule, and defines a movable seal with the interior surface of the capsule. The movable seal separates the osmopolymer from the protein or peptide. The piston has a recess that receives at least a portion of the osmotic agent. The osmotic agent imbibes liquid from a surrounding environment to cause the piston to move and, in turn, cause delivery of the beneficial agent from the capsule.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 10/959,489,filed Oct. 5, 2004, now U.S. Pat. No. 6,997,922, issued Feb. 14, 2006,which application is a continuation of application Ser. No. 10/354,142,filed Jan. 30, 2003, now U.S. Pat. No. 6,872,201, issued Mar. 29, 2005,which is a continuation of, and claims priority from U.S. patentapplication Ser. No. 09/472,600, filed Dec. 27, 1999, now U.S. Pat. No.6,544,252, issued Apr. 8, 2003, which claims the benefit of U.S.Provisional Application Ser. No. 60/114,548, filed on Dec. 31, 1998, theentire disclosures of which are hereby incorporated herein by referencein their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to osmotic delivery systems for deliveringbeneficial agents, and more particularly, to an osmotic delivery systemhaving a piston with a recess for receiving an osmotic agent.

2. Description of the Related Art

Controlled delivery of beneficial agents, such as drugs, in the medicaland veterinary fields, has been accomplished by a variety of methods.One method for controlled prolonged delivery of beneficial agentsinvolves the use of osmotic delivery systems. These devices can beimplanted to release beneficial agents in a controlled manner over apreselected time or administration period. In general, osmotic deliverysystems operate by imbibing liquid from the outside environment andreleasing corresponding amounts of the beneficial agent.

A known osmotic delivery system, commonly referred to as an “osmoticpump,” generally includes some type of capsule or enclosure having asemipermeable portion that may selectively pass water into an interiorof the capsule that contains a water-attracting osmotic agent. In such aknown osmotic delivery system, the walls of the capsule aresubstantially impermeable to items within and outside the capsule, and aplug acts as the semipermeable portion. The difference in osmolaritybetween the water-attracting agent and the exterior of the capsulecauses water to pass through the semipermeable portion of the capsule,which in turn causes the beneficial agent to be delivered from thecapsule through the delivery port. The water-attracting agent may be thebeneficial agent delivered to the patient. However, in most cases, aseparate osmotic agent is used specifically for its ability to drawwater into the capsule.

In some instances, a piston is required to separate the beneficial agentfrom the osmotic agent to prevent the osmotic agent from mixing with orcontaminating the beneficial agent. The structure of the capsule is suchthat the capsule does not expand when the osmotic agent takes in waterand expands. As the osmotic agent expands, pressure causes the piston tomove and the beneficial agent to be discharged through the deliveryorifice at the same rate as the liquid, which is typically water, entersthe osmotic agent by osmosis. Osmotic delivery systems may be designedto deliver a beneficial agent at a controlled constant rate, a varyingrate, or in a pulsatile manner.

In those osmotic delivery systems that require the use of a piston toseparate the beneficial agent and the osmotic agent, the pistonnecessarily occupies space in the capsule. Hence, if the piston isneeded to separate the beneficial agent and the osmotic agent, and thesize of the capsule is not changed, the amount of beneficial agent orosmotic agent that can be held within the capsule decreases as comparedto another osmotic delivery system having the same size capsule thatdoes not include a piston. Decreasing the amount of beneficial agentwithin the capsule detrimentally decreases the net amount of beneficialagent that can be delivered over a sustained period of time. Decreasingthe amount of osmotic agent within the capsule detrimentally decreasesthe sustained period of time through which continuous delivery of thebeneficial agent can be obtained.

But if the specific application requires a specific amount of beneficialagent or osmotic agent that cannot be varied and a piston must be usedto separate the beneficial agent from the osmotic agent, the size of thecapsule must be increased to accommodate for the extra space occupied bythe piston such that the amount of osmotic agent or beneficial agent inthe capsule does not vary. While simply increasing the size or volume ofthe capsule to accommodate for the extra volume occupied by the pistonmay appear to be a simple solution, because many osmotic deliverysystems are destined for implantation in humans or animals, it isespecially desirable to decrease the size of the osmotic delivery systemas much as possible, while still allowing the osmotic delivery system todeliver the beneficial agent over a prolonged period of time.Additionally, simply increasing the size of the capsule for thoseapplications requiring a piston that separates the beneficial agent fromthe osmotic agent is inexpedient as it is desirable to use one capsulefor multiple osmotic delivery system applications. Moreover, it has beenparticularly problematic to increase the amount of time over whichsteady state release of the beneficial agent may be obtained withcurrent osmotic delivery systems incorporating conventional pistons,without increasing the size of the capsule to hold more beneficial agentor osmotic agent. These problems associated with current osmoticdelivery systems having known pistons have created a need for asolution.

BRIEF SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, an osmoticdelivery system includes an enclosure having an interior for holding aprotein or peptide. An osmotic agent is located in the enclosure, and asemipermeable body is in liquid communication with the enclosure forpermitting liquid to permeate through the semipermeable body to theosmotic agent. The system also includes a piston located within theenclosure, the piston defining a movable seal with the enclosure thatseparates the osmotic agent from the protein or peptide. The piston hasa recess that receives a sleeve. The sleeve has an interior thatreceives at least a portion of the osmotic agent. The osmotic agent islocated between the piston and the semipermeable body, the osmotic agentadapted to imbibe liquid from a surrounding environment through thesemipermeable body to cause the piston to move and cause delivery of theprotein or peptide from the enclosure.

In accordance with another aspect of the present invention, an osmoticdelivery system includes a piston located within an enclosure, thepiston having a recess. The system also includes an osmotic agentlocated within the recess, the osmotic agent adapted to imbibe liquidfrom a surrounding environment to cause the piston to move within theenclosure and displace the contents of the enclosure.

According to another aspect of the present invention, a piston for usein an osmotic delivery system that has an enclosure and a semipermeablebody in communication with the enclosure includes a sleeve locatedwithin a recess in the piston, the sleeve having an interior. An osmoticagent is at least partially contained in the sleeve and is locatedbetween the piston and the semipermeable body. The osmotic agent isadapted to imbibe liquid from a surrounding environment through thesemipermeable body to cause the piston to move and cause delivery of thebeneficial agent from the enclosure.

Other objects, advantages and features associated with the presentinvention will become readily apparent to those skilled in the art fromthe following detailed description. As will be realized, the inventionis capable of other and different embodiments, and its several detailsare capable of modification in various obvious aspects, all withoutdeparting from the invention. Accordingly, the drawings and thedescription are to be regarded as illustrative in nature, and notlimiting.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The invention will be described in greater detail with reference to theaccompanying drawings in which like elements bear like referencenumerals, and wherein:

FIG. 1 is a sectional view of an osmotic delivery system according toone embodiment of the present invention;

FIG. 2 is a sectional view of an osmotic delivery system according tothe present invention taken along the line 2—2 of FIG. 1;

FIG. 3 is a perspective view of a piston according to one embodiment ofthe present invention;

FIG. 4 is an exploded perspective view of an osmotic delivery systemaccording to one embodiment of the present invention;

FIG. 5 is a sectional view of another osmotic delivery system accordingto the present invention;

FIG. 6 is a perspective view of a cup-shaped sleeve for insertion into arecess of a piston in accordance with another embodiment of the presentinvention; and

FIG. 7 is sectional view of the sleeve of FIG. 6 taken along the line7—7 of FIG. 6.

DETAILED DESCRIPTION OF THE INVENTION

As shown in FIGS. 1–4, the present invention relates to an osmoticdelivery system 20 for delivering a beneficial agent 24. The osmoticdelivery system 20 includes a “space-efficient” piston 30. The piston 30includes a recess 34 that receives an osmotic agent 26. The osmoticdelivery system 20 also includes an enclosure 21 that encloses thepiston 30 and the osmotic agent 26. The piston 30 is movable within theenclosure 21 and defines a movable seal that substantially prevents theosmotic agent 26 and the beneficial agent 24 from adversely affectingone another. A semipermeable body 28 is in liquid communication with theosmotic agent 26 and permits liquid to permeate through thesemipermeable body 28 to the osmotic agent 26. The osmotic agent 26imbibes the liquid from a surrounding environment and causes the piston30 to move, which, in turn, causes the beneficial agent 24 to bereleased from the osmotic delivery system 20.

The configuration of the osmotic delivery system 20 according to thepresent invention illustrated in FIGS. 1–4 is one example of an osmoticdelivery device and is not to be construed as limiting the presentinvention. The present invention is generally applicable to all osmoticdelivery devices having any number of shapes, and to all such devicesadministered in any variety of methods, such as oral, ruminal, andimplantable osmotic delivery techniques. Such devices may also be placedin reservoirs, tanks, or pools.

The enclosure 21 of the osmotic delivery system 20 encloses or containsthe osmotic agent 26 and the body 32 of the piston 30 (shown in FIG. 3).The enclosure 21 includes a tubular or elongated and substantiallycylindrical capsule 22 illustrated in FIGS. 1 and 4. The capsule 22 hasa first opening 51 at a first end 50 and a second opening 53 at a secondend 52 opposite the first end 50. The enclosure 21 also includes thesemipermeable body 28 that obstructs, blocks, closes-off, or plugs thefirst opening 51 in the capsule 22 to enclose the osmotic agent 26 andbody 32 of piston 30. Thus, the first opening 51 receives thesemipermeable body 28.

The enclosure 21 also includes a delivery port 44 located at the secondend 52 of the capsule 22. The delivery port 44 delivers the beneficialagent 24 from the osmotic delivery system 20. According to otherembodiments of the present invention, the capsule 22 may take differentforms and shapes. For example, the capsule 22 can be tablet-shaped, havean elliptical cross-section, and can be formed from multiple piece tubesor cylinders, or two spheroidal sections. Additionally, the secondopening 53 of the capsule 22 can define the delivery port 44, and thefirst opening 51 can define a channel for communicating a liquid, suchas water, from a semipermeable body external of the capsule 22 to anosmotic agent within the capsule. The first opening 51 can also define achannel for communicating a liquid from an external environment to asemipermeable body within the capsule 22.

The delivery port 44 is an orifice formed by conventional techniques.Included among these methods are mechanical drilling, laser drilling,and molding. The enclosure 21 will contain at least one such deliveryport 44, and in most configurations, one delivery port will suffice.However, two or more delivery ports 44 may be present without departingfrom the present invention. The delivery port 44 may be formed in thecapsule 22 itself, such as in the embodiment illustrated in FIG. 5(shown as 144 and 122, respectively), or may be formed in a separate anddistinct plug-like member 42 having means for sealing or ribs 48extending outwardly from the outer surface thereof for insertion intothe second opening 53 of the capsule 22. The delivery port 44 can beother configurations. For example, the delivery port 44 can be a slitorifice, such as that disclosed in U.S. application Ser. No. 09/045,944,now U.S. Pat. No. 5,997,527, issued Dec. 7, 1999, the entire disclosureof which is hereby incorporated herein by reference, or a spiralorifice, such as that disclosed in U.S. application Ser. No. 08/595,761,the entire disclosure of which is hereby incorporated herein byreference.

The dimensions of the port 44 in terms of both diameter and length willvary with the type of beneficial agent 24, the rate at which thebeneficial agent is to be delivered, and the environment into which itis to be delivered. The considerations involved in determining theoptimum dimensions of the delivery port 44 for any particular enclosureor beneficial agent 24 are the same as those for delivery ports ororifices of enclosures of the prior art, and selection of theappropriate dimensions will be readily apparent to those skilled in theart.

The capsule 22 is formed of a material that is sufficiently rigid towithstand expansion of an osmotic agent 26 without changing size orshape. The capsule 22 is preferably substantially impermeable to fluidsin the environment as well as to ingredients contained within theosmotic delivery system 20 such that the migration of such materialsinto or out of the capsule through the impermeable material of thecapsule is so low as to have substantially no adverse impact on thefunction of the osmotic delivery system 20.

Materials that can be used for the capsule 22 are preferablysufficiently strong to ensure that the capsule will not leak, crack,break, or distort under stresses to which it would be subjected duringimplantation or under stresses due to the pressures generated duringoperation of the osmotic delivery system 20.

The capsule 22 can be formed of chemically inert and biocompatible,natural or synthetic materials that are known in the art. The capsulematerial is preferably a non-bioerodible material that can remain in apatient after use, such as titanium or a titanium alloy, and is largelyimpermeable to materials within and outside the capsule 22. However, thematerial of the capsule 22 can alternatively be a bioerodible materialthat bioerodes in the environment after dispensing the beneficial agent24. Generally, preferred materials for the capsule 22 are thoseacceptable for human implants.

In general, typical materials of construction suitable for the capsule22 include non-reactive polymers or biocompatible metals or alloys. Thepolymers include acrylonitrile polymers such asacrylonitrile-butadiene-styrene terpolymer, and the like; halogenatedpolymers such as polytetrafluoroethylene, polychlorotrifluoroethylene,copolymer tetrafluoroethylene and hexafluoropropylene polyimide;polysulfone; polycarbonate; polyethylene; polypropylene;polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and thelike. Metallic materials useful for the capsule 22 include stainlesssteel, titanium, platinum, tantalum, gold, and their alloys, as well asgold-plated ferrous alloys, platinum-plated ferrous alloys,cobalt-chromium alloys and titanium nitride coated stainless steel. Thecapsule 22 can be formed from any of the above-mentioned wall-formingmaterials by the use of a mold, with the materials applied either overthe mold or inside the mold, depending on the mold configuration.Additionally, the capsule 22 can be formed by machining. Any of the widevariety of techniques known in the pharmaceutical industry can be usedto form the capsule 22.

The interior of the capsule 22 receives the osmotic agent 26, which inthe embodiment of the present invention depicted in FIGS. 1 and 4 is anosmotic tablet. The osmotic agent 26, specifically the osmotic tablet ofthe embodiment of the present invention illustrated in FIG. 1, drivesthe osmotic flow of the osmotic delivery system 20. The osmotic agent 26need not be a tablet; it may be other conceivable shapes, textures,densities, and consistencies and still be within the confines of thepresent invention. Additionally, more than one osmotic tablet may beused to drive the osmotic flow of the osmotic delivery system 20. Whenthe osmotic delivery system 20 is assembled, the capsule 22 contains theosmotic agent 26.

The osmotic agent 26 is a liquid-attracting agent used to drive the flowof the beneficial agent 24 from the osmotic delivery system 20. Theosmotic agent 26 may be an osmagent, an osmopolymer, or a mixture of thetwo. Species that fall within the category of osmagent, i.e., thenon-volatile species which are soluble in water and create the osmoticgradient driving the osmotic inflow of water, vary widely. Examples arewell known in the art and include magnesium sulfate, magnesium chloride,potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate,sodium phosphate, potassium phosphate, d-mannitol, sorbitol, inositol,urea, magnesium succinate, tartaric acid, raffinose, and variousmonosaccharides, oligosaccharides and polysaccharides such as sucrose,glucose, lactose, fructose, and dextran, as well as mixtures of any ofthese various species.

Species that fall within the category of osmopolymer are hydrophilicpolymers that swell upon contact with water, and these vary widely aswell. Osmopolymers may be of plant or animal origin, or synthetic, andexamples of osmopolymers are well known in the art. Examples include:poly(hydroxy-alkyl methacrylates) with molecular weight of 30,000 to5,000,000, poly(vinylpyrrolidone) with molecular weight of 10,000 to360,000, anionic and cationic hydrogels, polyelectrolyte complexes,poly(vinyl alcohol) having low acetate residual, optionally cross-linkedwith glyoxal, formaldehyde or glutaraldehyde and having a degree ofpolymerization of 200 to 30,000, a mixture of methyl cellulose,cross-linked agar and carboxymethylcellulose, a mixture of hydroxypropylmethylcellulose and sodium carboxymethylcellulose, polymers ofN-vinyllactams, polyoxyethylene-polyoxypropylene gels,polyoxybutylene-polyethylene block copolymer gels, carob gum,polyacrylic gels, polyester gels, polyurea gels, polyether gels,polyamide gels, polypeptide gels, polyamino acid gels, polycellulosicgels, carbopol acidic carboxy polymers having molecular weights of250,000 to 4,000,000, Cyanamer polyacrylamides, cross-linkedindene-maleic anhydride polymers, Good-Rite® polyacrylic acids havingmolecular weights of 80,000 to 200,000, Polyox Polyethylene oxidepolymers having molecular weights of 100,000 to 5,000,000, starch graftcopolymers, and Aqua-Keeps acrylate polymer polysaccharides.

The osmotic agent 26 may be manufactured by a variety of techniques,many of which are known in the art. In one such technique, anosmotically active agent is prepared as solid or semi-solid formulationsand pressed into pellets or tablets whose dimensions correspond toslightly less than the internal dimensions of the respective chamberswhich they will occupy in the capsule interior. Depending on the natureof the materials used, the agent and other solid ingredients that may beincluded, can be processed prior to the formation of the pellets by suchprocedures as ballmilling, calendaring, stirring or rollmilling toachieve a fine particle size and hence fairly uniform mixtures of each.

The beneficial agent 24 may optionally include pharmaceuticallyacceptable carriers and/or additional ingredients such as antioxidants,stabilizing agents, permeation enhancers, etc. In other embodiments ofthis invention, the beneficial agent 24 contained in the capsule 22 mayinclude flowable compositions such as liquids, suspension, or slurries,which are typically poured into the capsule after the osmotic agent 26and the body 32 of the piston 30 have been inserted in the capsule.

Patients to whom beneficial agents 24 may be administered using systemsof this invention include humans and animals. The invention is ofparticular interest for application to humans and household, sport, andfarm animals, particularly mammals. For the administration of beneficialagents, the devices of the present invention may be implantedsubcutaneously or intraperitoneally wherein aqueous body fluids orliquids are available to activate the osmotic agent 26. Devices of theinvention may also be administered to the rumen of humans and ruminantanimals, in which embodiment the devices may further comprise aconventional density element for maintaining the device in the rumen forextended periods of time of up to 120 days or longer.

The present invention applies to the administration of beneficial agentsin general, which include any physiologically or pharmacologicallyactive substance. The beneficial agent 24 may be any of the agents thatare known to be delivered to the body of a human or an animal such asmedicaments, vitamins, nutrients, or the like. The beneficial agent 24may also be an agent that is delivered to other types of aqueousenvironments such as pools, tanks, reservoirs, and the like. Includedamong the types of agents that meet this description are biocides,sterilization agents, nutrients, vitamins, food supplements, sexsterilants, fertility inhibitors and fertility promoters.

Drug agents that may be delivered by the present invention include drugswhich act on the peripheral nerves, adrenergic receptors, cholinergicreceptors, the skeletal muscles, the cardiovascular system, smoothmuscles, the blood circulatory system, synoptic sites, neuroeffectorjunctional sites, endocrine and hormone systems, the immunologicalsystem, the reproductive system, the skeletal system, autacoid systems,the alimentary and excretory systems, the histamine system and thecentral nervous system. Suitable agents may be selected from, forexample, proteins, enzymes, hormones, polynucleotides, nucleoproteins,polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids,analgesics, local anesthetics, antibiotic agents, anti-inflammatorycorticosteroids, ocular drugs and synthetic analogs of these species.

Examples of drugs that may be delivered by devices according to thisinvention include, but are not limited to, prochlorperzine edisylate,ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride,procainamide hydrochloride, amphetamine sulfate, methamphetaminehydrochloride, benzamphetamine hydrochloride, isoproterenol sulfate,phenmetrazine hydrochloride, bethanechol chloride, methacholinechloride, pilocarpine hydrochloride, atropine sulfate, scopolaminebromide, isopropamide iodide, tridihexethyl chloride, phenforminhydrochloride, methylphenidate hydrochloride, theophylline cholinate,cephalexin hydrochloride, diphenidol, meclizine hydrochloride,prochlorperazine maleate, phenoxybenzamine, thiethylperzine maleate,anisindone, diphenadione erythrityl tetranitrate, digoxin,isoflurophate, acetazolamide, methazolamide, bendroflumethiazide,chlornronamide, tolazamide, chlormadinone acetate, phenaglycodol,allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole,erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisoneacetate, dexamethasone and its derivatives such as betamethasone,triamcinolone, methyltestosterone, 17-S-estradiol, ethinyl estradiol,ethinyl estradiol 3-methyl ether, prednisolone, 17-∝-hydroxyprogesteroneacetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone,norethiederone, progesterone, norgesterone, norethynodrel, aspirin,indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin,isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol,cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa,dihydroxyphenylalaline, theophylline, calcium gluconate, ketoprofen,ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrouslactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone,capropril, mandol, quanbenz, hydrochlorothiazide, ranitidine,flurbiprofen, fenufen, fluprofen, tolmetin, alciofenac, mefenamic,flufenamic, difuinal, nimodipine, nitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,mioflazine, lisinolpril, enalapril, enalaprilat, captopril, ramipril,famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chiordiazepoxide, diazepam, amitriptyline, and imipramine. Furtherexamples are proteins and peptides which include, but are not limitedto, insulin, coichicine, glucagon, thyroid stimulating hormone,parathyroid and pituitary hormones, calcitonin, renin, prolactin,corticotrophin, thyrotropic hormone, follicle stimulating hormone,chorionic gonadotropin, gonadotropin releasing hormone, bovinesomatotropin, porcine somatotropin, oxytocin, vasopressin, GRF,prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone,LHRH, LHRH agonists and antagonists, leuprolide, interferons,interleukins, growth hormones such as human growth hormone, bovinegrowth hormone and porcine growth hormone, fertility inhibitors such asthe prostaglandins, fertility promoters, growth factors, coagulationfactors, human pancreas hormone releasing factor, analogs andderivatives of these compounds, and pharmaceutically acceptable salts ofthese compounds, or their analogs or derivatives.

The beneficial agent 24 can be present in this invention in a widevariety of chemical and physical forms, such as solids, liquids andslurries. On the molecular level, the various forms may includeuncharged molecules, molecular complexes, and pharmaceuticallyacceptable acid addition and base addition salts such as hydrochlorides,hydrobromides, acetate, sulfate, laurylate, oleate, and salicylate. Foracidic compounds, salts of metals, amines or organic cations may beused. Derivatives such as esters, ethers and amides can also be used. Abeneficial agent can be used alone or mixed with other agents.

Osmotic delivery systems according to the present invention are alsouseful in environments outside of physiological or aqueous environments.For example, the osmotic delivery system may be used in intravenoussystems (attached to an IV pump or bag or to an IV bottle, for example)for delivering beneficial agents to an animal or human. Osmotic deliverysystems according to the present invention may also be utilized in bloodoxygenators, kidney dialysis and electrophoresis, for example.Additionally, devices or systems of the present invention may be used inthe biotechnology area, such as to deliver nutrients or growthregulating compounds to cell cultures. In such instances, activatingmechanisms such as mechanical mechanisms are particularly useful.

The osmotic delivery system 20 also includes the aforementionedsemipermeable body 28, such as the semipermeable plug illustrated inFIGS. 1 and 4. The semipermeable body 28 is formed of a semipermeablematerial that allows liquid to pass from an exterior environment of useinto the capsule 22 to cause the osmotic agent 26 to swell. But thematerial forming the semipermeable body 28 is largely impermeable to thematerials within the enclosure 21 and other ingredients within theenvironment of use. As illustrated in FIG. 1, the semipermeable body 28is in the shape of a plug that is inserted into the first opening 51 ofthe capsule 22 at the first end 50. The semipermeable body 28 definespart of the enclosure 21 because it closes-off the first opening 51 ofthe capsule 22. Alternatively, the semipermeable body 28 may be locateddistant from the enclosure 21, but communicate liquid from a surroundingenvironment of use to the osmotic agent 26 through a tube in liquidcommunication with the capsule 22 or through other means forcommunicating liquid. The semipermeable body 28 may also be a membranecoating on the exterior surface of the capsule 22 or a sleeve or capthat slides over a portion of the capsule 22 to enclose the osmoticagent 26.

As shown in FIG. 1, the osmotic delivery system 20 includes thesemipermeable body 28, such as the semipermeable plug illustrated. Thesemipermeable body 28 is typically cylindrically shaped, and has meansfor sealing or ribs 46 extending outwardly from the outer surface of thesemipermeable body 28. The ribs 46 are the means by which thesemipermeable plug operates like a cork or stopper, obstructing andplugging the opening 51 in the capsule 22 of the osmotic delivery system20 illustrated in FIG. 1. The means for sealing 46 may be the exemplaryribs, or may be other configurations such as threads, a tightinterference fit between an outer sealing surface of the plug and thecapsule 22, glue, adhesives, ridges, lips, or other devices which jointhe semipermeable body 28 with the capsule 22 to prevent leakage. Thesemipermeable body 28 is, therefore, intended for at least partialinsertion into an opening of the capsule 22, and the means for sealing46 the environment of use from an inside of the capsule 22 preventsliquid and other substances in the environment of use, besides thepermeation liquid, from entering the osmotic delivery system 20 whilealso preventing materials from the inside of the delivery system fromleaking or escaping to the environment of use.

The semipermeable body 28 is made from a semipermeable material. Thesemipermeable material of the body 28 allows liquids, especially water,to pass from an exterior environment of use into the capsule 22 to causethe osmotic agent 26 to swell. However, the semipermeable materialforming the semipermeable body 28 is largely impermeable to thematerials within the capsule 22 and other ingredients within the fluidenvironment.

Semipermeable compositions suitable for the semipermeable body 28 arewell known in the art, examples of which are disclosed in U.S. Pat. No.4,874,388, the entire disclosure of which is incorporated herein byreference. Such possible semipermeable materials from which the body 28can be made include, but are not limited to, for example, Hytrelpolyester elastomers (DuPont), cellulose esters, cellulose ethers andcellulose ester-ethers, water flux enhanced ethylene-vinyl acetatecopolymers, semipermeable membranes made by blending a rigid polymerwith water-soluble low molecular weight compounds, and othersemipermeable materials well known in the art. The above cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucoseunit, from greater than 0 up to 3 inclusive. By, “degree ofsubstitution,” or “D.S.,” is meant the average number of hydroxyl groupsoriginally present on the anhydroglucose unit comprising the cellulosepolymer that is replaced by a substituting group. Representativematerials include, but are not limited to, one selected from the groupconsisting of cellulose acylate, cellulose diacetate, cellulosetriacetate, mono-, di-, and tricellulose alkanylates, mono-, di-, andtricellulose aroylates, and the like. Exemplary cellulosic polymersinclude cellulose acetate having a D.S. up to 1 and an acetyl content upto 21%; cellulose acetate having a D.S. of 1 to 2 and an acetyl contentof 21% to 35%; cellulose acetate having a D.S. of 2 to 3 and an acetylcontent of 35% to 44.8%, and the like. More specific cellulosic polymersinclude cellulose propionate having a D.S. of 1.8 and a propionylcontent of 39.2% to 45% and a hydroxyl content of 2.8% to 5.4%;cellulose acetate butyrate having a D.S. of 1.8 and an acetyl content of13% to 15% and a butyryl content of 34% to 39%; cellulose acetatebutyrate having an acetyl content of 2% to 29%, a butyryl content of 17%to 53% and a hydroxyl content of 0.5% to 4.7%; cellulose acetatebutyrate having a D.S. of 1.8, and acetyl content of 4 average weightpercent and a butyryl content of 51%; cellulose triacylates having aD.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate,cellulose tripalmitate, cellulose trisuccinate, and cellulosetrioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6 such ascellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate,cellulose dipentate; coesters of cellulose such as cellulose acetatebutyrate and cellulose, cellulose acetate propionate, and the like.

Other materials for the semipermeable body 28 are polyurethane,polyetherblockamide (PEBAX, commercially available from ELF ATOCHEM,Inc.), injection-moldable thermoplastic polymers with somehydrophilicity such as ethylene vinyl alcohol (EVA). The composition ofthe semipermeable body 28 is permeable to the passage of externalliquids such as water and biological liquids, and it is substantiallyimpermeable to the passage of beneficial agents, osmopolymers,osmagents, and the like.

The osmotic delivery system 20 also includes the movable space-efficientpiston 30. The piston 30 is a member that is matingly received by thehollow interior of the capsule 22 and moves when subjected to pressurefrom the osmotic agent 26 to displace or move the beneficial agent 24.The piston 30 forms a movable seal with the interior surface of thecapsule 22. The movable seal formed by the piston 30 separates theosmotic agent 26 and the beneficial agent 24 such that the osmotic agent26 does not substantially leak or seep past the piston seal andadversely affect the function of the beneficial agent 24. Hence, theosmotic agent 26 is separated from the beneficial agent 24 by themovable piston 30.

As illustrated in FIG. 3, the body 32 of the piston 30 is asubstantially cylindrical member that is configured to fit in thecapsule 22 in a sealing manner that allows the piston 30 to slide withinthe capsule 22 in the longitudinal direction of the capsule 22. That is,the exterior surface of the piston body 32 abuts against and slidesrelative to the interior cylindrical surface of the capsule 22. Becausethe semipermeable body 28 is lodged within the first opening 51, thepiston 30 also moves relative to the semipermeable body 28.

The piston body 32 includes annular ring-shaped protrusions or ribs 38that define the movable or sliding seal with the inner surface of thecapsule 22. The ribs 38 are the most outwardly radial surface of thepiston body 32. The ribs 38 are the means by which the piston 30 forms aseal with the interior surface of the capsule 22. Thus, the outermostradial diameter of the piston body 32 is greater than the inner diameterof the capsule 22. Although the piston body 32 illustrated in FIG. 3includes two ribs, other pistons according to the present invention mayinclude one or more ribs. Additionally, the piston body 32 need notinclude ribs. For example, the exterior surface of the piston body canbe entirely cylindrical such that the entire cylindrical exteriorsurface of the piston body effects a seal with the interior surface ofthe capsule 22. However, the ribs 38 are preferred as they effect abetter movable seal with the interior surface of the capsule 22, ascompared to a piston body having an exterior surface that is entirelycylindrical. The piston body 32 is preferably formed of an impermeableresilient and inert material. In general, materials suitable for thepiston body 32 are elastomeric materials including the non-reactivepolymers listed above in reference to the materials for the capsule 22,as well as elastomers in general, such as polyurethanes and polyamides,chlorinated rubbers, styrene-butadiene rubbers, and chloroprene rubbers.

As illustrated in FIG. 3, the piston body 32 includes a hollow interiorportion or recess 34, such as the cylindrical cavity illustrated. Therecess 34 can be other configurations such as a square cavity, concaveindentation, conical pit, cup, gouge, depression, or similar spaceadapted to receive the osmotic agent 26. The recess 34 has a cylindricaland longitudinal interior surface 33 that begins at an insert opening 31formed by the recess 34 in the first end 35 of the piston body 32, andends at a depth surface 36 within the piston body 32 close to the secondend 37 of the piston body 32. Because of the general cylindrical shapeof the outer surface of the piston body 32 and the cylindrical shape ofthe recess 34, the piston is thimble or cup-shaped such that a “bottomof the cup” has a thickness. Because the piston 30 separates thebeneficial agent 24 and the osmotic agent 26, the recess 34 preferablydoes not pierce completely through the piston body 32. The piston body32 is cup-shaped because the recess 34 defines a hollow area within thepiston body 32.

The longitudinal axis of the recess 34 is approximately parallel to thelongitudinal axis of the capsule 22, and is preferably coincident withthe longitudinal axis of the capsule 22. Additionally, the opening 31 ofthe recess 34 faces away from the delivery port 44, i.e., toward thesemipermeable body 28. The depth surface 36 of the recess preferablyextends past the median of the piston body 32 along the longitudinalaxis of the piston as measured from the first end 35. The diameter ofthe recess 34 is typically 50%, preferably greater than 60%, andpreferably less than 80% of the inner diameter of the capsule 22. Byincreasing the diameter of the recess 34, the wall thickness of thepiston body 32 decreases. It is preferable that the recess 34 occupy asmuch internal volume of the piston 30 as possible without destroying theeffectiveness of the piston seal when the piston 30 is inserted into thecapsule 22. Additionally, the exterior surface of the piston body 32 cantake other shapes, such as a chevron or cantilever shape.

Although the cylindrical configuration of the recess 34 is preferred,other configuration recesses fall within the confines of the presentinvention. For example, the recess 34 or hollow interior portion may besquare, rectangular, octagonal, triangular, oval, half-circular,circular, or a shape that matches the shape of the exterior surface ofthe piston body 32. Likewise, the recess 34 may be a series or pluralityof recesses, tubes, slots, or gaps within the interior of the pistonbody 32. All of the above, and other configurations, would function toreceive a portion of the osmotic agent 26 such that the piston 30occupies less space within the capsule 22.

The recess 34 of the piston body 32 receives the osmotic agent 26, suchas the osmotic tablet illustrated in FIG. 1. Additionally, the recess 34also matingly receives an insert or sleeve 40, such as the cylindricaltube illustrated in FIGS. 1 and 2. The sleeve 40 is preferably made froma rigid and impermeable material such as that used for the capsule 22,and helps effect a movable seal between the piston and the interiorsurface of the capsule 22. For example, the sleeve 40 can be formed frompolycarbonate, polysulfone, polystyrene, or an acetal such as DELRIN®(DuPont). The sleeve 40 also can be made out of an inert metal such asstainless steel or titanium. The sleeve 40 is inserted into the recess34 and has an outer diameter that at least matches the diameter of therecess 34. Because the recess 34 receives the sleeve 40, it ispreferable that the shape of the exterior surface of the sleeve 40matches or corresponds to the shape of the recess 34. For example, therecess 34 and the sleeve 40 are both cylindrical. It is also preferablethat the wall-thickness of the sleeve 40 be thin so as to occupy littlespace within the recess 34. In general, the wall-thickness of the sleeve40 must be thick enough to impart enough rigidity to the sleeve tomaintain the piston seal with the interior surface of the capsule 22.

The sleeve 40 is sized such that the recess 34 matingly receives thesleeve 40. In instances where it is desirable to increase the outerdiameter of the piston body 32, if the piston body 32 is formed of aresilient material, the outer diameter of the sleeve 40 may be greaterthan the diameter of the recess 34 such that the piston body 32 deflectsradially and outwardly when the sleeve 40 is inserted therein. In theembodiment illustrated in FIG. 1, the longitudinal length of the sleeve40 is substantially equal to the longitudinal depth of the recess 34 inthe piston body 32.

It will be appreciated that the sleeve 40 may be in any number ofdifferent shapes and sizes, but preferably matches the shape and size ofthe recess 34 into which the sleeve 40 is inserted. For example, thesleeve 40 may be cup-shaped or shaped like a chevron. In general, thesleeve 40 stabilizes the dimensions and sealing forces of the pistonbody 32 as the piston moves, especially if an osmotic tablet is usedthat dissolves into a fluid during operation of the osmotic deliverysystem 20. Additionally, the sleeve 40 helps prevent the beneficialagent 24 from diffusing into the osmotic agent 26 during storage of theosmotic delivery device 20.

The sleeve 40 is preferably inserted into the recess 34 for assistingthe piston body 32 in effecting a movable seal with the interior surfaceof the capsule 22. Because the piston body 32 is preferably flexible andresilient, the wall of the piston body 32 flexes toward the interior ofthe recess 34 after the piston body 32 is inserted into the capsule 22.By inserting the preferably rigid sleeve 40 into the opening 31 of therecess 34 such that the sleeve 40 is matingly received,.the wall of thepiston body 32 will not overly flex inwardly toward the recess 34, andthe seal formed between the outer surface of the piston 30 and theinterior surface of the capsule 22 is maintained.

FIGS. 6 and 7 illustrate another embodiment of a sleeve. As shown byFIGS. 6 and 7, the sleeve 240 is in the shape of cup, such as a cap orthimble. The sleeve 240 is inserted into the piston body 232, and theosmotic agent 226 is inserted in the recess formed by the cup-shapedsleeve 240. The sleeve 240 may be fabricated from an inert and rigidmaterial to ensure that the piston is impermeable.

Although the piston 30 illustrated in FIG. 1 includes the sleeve 40, insome instances, it may not be necessary to include the sleeve 40 in therecess 34 as the material of the piston body 32 is sufficiently rigid toeffect a satisfactory seal between the interior surface of the capsule22 and the piston body 32. In this case, the sleeve 40 need not beinserted into the recess 34. Generally, the wall thickness and thestructural characteristics of the piston body 32 determine whether ornot a rigid sleeve 40 is needed to assist in defining the seal, which isdeterminable by experimental methods.

The osmotic agent 26 is at least partially located within the recess 34.Preferably, the majority of the total weight of the osmotic agent 26 islocated within the recess 34. The osmotic agent 26 may be completelylocated within the recess 34, or may extend partially from the recess34. As illustrated in FIG. 1, the volume of the osmotic agent 26 isgreater than that of the recess 34 such that the osmotic agent extendsfrom the recess 34 and into a gap or space 54 located between the piston30 and the semipermeable body 28. The osmotic agent 26 may completelyfill the gap 54 such as shown in FIG. 5, or only partially fill the gap54, as shown in FIG. 1.

The piston body 32 is preferably injection molded. However, the pistonbody 32 may be fashioned by a different process. For example, the pistonbody 32 may also be made from extrusion, reaction injection molding,rotational molding, thermoforming, compression molding, and other knownprocesses. If an injection molding process is used to form the pistonbody 32, the ejector pin or core may be used to form the recess 34, anddifferent length and sized ejector pins or cores may be easily changedto fashion different size recesses 34 to controllably vary the amount ofosmotic agent that is received by the recess 34 of the piston 30.Additionally, the recess 34 may be formed in the piston body 32 afterthe piston body has been formed without a recess. For example, acylinder of material may be fabricated and sliced into smallercylinders. Thereafter, a cylindrical section may be removed from thepiston body to form the recess 34 in the piston body 32.

Furthermore, the piston body 32 need not be the unitary structureillustrated in FIG. 3. A cylindrical tube may be attached to a flatcircular disk to define the cup-shape of the piston 30. Additionally,the sleeve 40 may be cup-shaped, and a resilient tube with ribs may wraparound an outer cylindrical surface of the sleeve to define the piston30.

It is preferable that the piston body 32 be substantially impervious toliquids, such that the osmotic agent and the liquid that permeatesthrough the semipermeable body 28 does not diffuse through the pistonbody 32 and affect the beneficial agent 24 located on the side of thepiston 30 opposite from that of the osmotic agent 26, and such that thebeneficial agent does not diffuse through the piston body 32 and affectthe performance of the osmotic agent 26.

Because the recess 34 of the piston body 32 at least receives a portionof the osmotic agent 26, the total volume of the osmotic delivery system20, as compared to past systems, may be efficiently utilized. That is,rather than locating the osmotic agent 26 entirely between asemipermeable body and a known piston having no recess, the osmoticagent is at least partially located within the piston such that thespace within the capsule 22 is efficiently utilized. The space-efficientpiston 30 occupies less space in the capsule 22 of the osmotic deliverysystem 20, as compared to conventional pistons. Because the piston 30occupies less space within the capsule 22, the internal volume of theinterior of the capsule 22 need not be overly increased, if increased atall, to accommodate for the extra space occupied by the piston such thatthe amount of osmotic agent or beneficial agent in the capsule does notexcessively vary when the piston 30 is used. This characteristic of theosmotic delivery system 20 increases the amount of time over whichsteady-state release of the beneficial agent 24 may be obtained ascompared to past osmotic delivery systems that include conventionalpistons. Additionally, because the piston 30 occupies less volume thanpast pistons, the total internal volume of the capsule 22 of the osmoticdelivery system 20 can be decreased to provide an enclosure that is moresuitable for human or animal implantation.

The piston 30 can also be used with existing osmotic delivery systemsthat utilize conventional pistons to increase the duration of continuousor pulsatile delivery of a beneficial agent from the osmotic deliverysystem. This is because the recess 34 can receive additional osmoticagent or because the existing osmotic agent can be located within therecess 34 so that the delivery system can hold additional beneficialagents. The factors that determine how much osmotic agent is needed toobtain sustained release of beneficial agents from osmotic deliverysystems are described in a publication by F. Theeuwes and S. I. Yum,Principles of the Design and Operation of Generic Osmotic Pumps for theDelivery of Semisolid or Liquid Drug Formulations, ANNALS OF BIOMEDICALENGINEERING 41, 1976, at 343–353, the entire disclosure of which ishereby incorporated herein by reference.

In assembling the osmotic delivery system 20 according to one embodimentof the present invention, the sleeve 40 is first inserted into therecess 34 of the piston 30. Then, the piston 30 is inserted into thefirst opening 51 of the capsule 22. Once the osmotic agent pellet ortablet has been formed, it is placed inside the recess 34 such that thehollow interior 41 of the sleeve 40 receives the osmotic agent 26. Ifthe osmotic agent is a powder formulation, it can be poured into therecess 34. After the osmotic agent is located within the capsule 22, thesemipermeable body 28 is inserted into the first opening to close-offthe first end 50 of the capsule 22. At this stage of the assemblyprocess, the osmotic agent 26 is located between the semipermeable body28 and the piston body 32. The beneficial agent 24 is then inserted intothe second opening 53 of the capsule 22 such that the beneficial agentis directly adjacent to the piston 30. Thereafter, the plug-like member42 having means for sealing or ribs 48 extending outwardly from theouter surface thereof is inserted into the second opening to close-offthe second end of the capsule 22 and complete the osmotic deliverysystem 20.

FIG. 5 illustrates an alternative embodiment of an osmotic deliverysystem 120 according to the present invention. The foregoing andfollowing discussion of the benefits and function of the osmoticdelivery system 20 also applies to the osmotic delivery system 120.Thus, the osmotic delivery system illustrated in FIG. 5 has beenassigned corresponding reference numbers as the osmotic delivery system20, increased by 100. The osmotic delivery system 120 illustrated inFIG. 5 also includes many additional features and inherent functions asdescribed further below.

As illustrated in FIG. 5, the osmotic delivery system 120 includes anelongated substantially cylindrical capsule 122 having an openingthrough which a semipermeable body 128 has been inserted. Thesemipermeable body 128 is a cup-shaped membrane that has been insertedinto an opening in the first end 150 of the capsule 122.

Also located within the capsule 122 is the osmotic agent 126, which is apowder formulation. The osmotic agent 126 is received by the recess ofthe piston body 132, as is the sleeve 140. Because the osmotic agent 126is a powder formulation, it generally occupies the entire space or gapbetween the piston body 132 and the semipermeable body 128. Thus, thepowder formulation of the osmotic agent efficiently utilizes the spacebetween the piston body 132 and the semipermeable body 128.

The capsule 122 of the osmotic delivery system 120 defines a deliveryport 144 at the second end 152. Attached to the delivery port 144 is acatheter or tube 160 that delivers the beneficial agent 124 dispensedfrom the capsule 122 to a remote location. Hence, the osmotic deliverysystem 120 does not include a plug-like member having a delivery port 44such as the plug-like member 42 shown in FIG. 1. Protrusions or ribs 138of the piston body 132 seal the beneficial agent 124 from the osmoticagent 126.

While the invention has been described in detail with reference to apreferred embodiment thereof, it will be apparent to one skilled in theart that various changes can be made, and equivalents can be employedwithout departing from the spirit and scope of the invention.

1. An osmotic delivery system comprising: a piston located within anenclosure, the piston having a recess and at least one rib for effectinga movable seal with the enclosure; and an osmotic agent located withinthe recess, the osmotic agent for imbibing liquid from a surroundingenvironment to cause the piston to move within the enclosure anddisplace contents of the enclosure.
 2. The osmotic delivery systemaccording to claim 1, wherein the piston comprises an elastomericmaterial.
 3. The osmotic delivery system according to claim 1, whereinthe piston comprises a material selected from the group consisting ofpolyurethanes, polyamides, chlorinated rubbers, styrene-butadienerubbers, and chloroprene rubbers.
 4. A piston for use in an osmoticdelivery system having an enclosure and a semipermeable body incommunication with the enclosure, the piston comprising: a sleevelocated within a recess in the piston, the sleeve having an interior; anosmotic agent at least partially contained in the sleeve, the osmoticagent located between the piston and the semipermeable body, the osmoticagent for imbibing liquid from a surrounding environment through thesemipermeable body to cause the piston to move and cause delivery of thebeneficial agent from the enclosure.
 5. The osmotic delivery systemaccording to claim 4, wherein the piston includes at least one rib foreffecting a movable seal with the enclosure.
 6. The osmotic deliverysystem according to claim 4, wherein the piston comprises an elastomericmaterial.
 7. An osmotic delivery system comprising: an enclosure havingan interior for holding a protein or peptide, an osmotic agent locatedin the enclosure, and a semipermeable body in liquid communication withthe enclosure for permitting liquid to permeate through thesemipermeable body to the osmotic agent; and a piston located within theenclosure, the piston defining a movable seal with the enclosure thatseparates the osmotic agent from the protein or peptide, the pistonhaving a recess that receives a sleeve having an interior that receivesat least a portion of the osmotic agent, the osmotic agent locatedbetween the piston and the semipermeable body, the osmotic agent forimbibing liquid from a surrounding environment through the semipermeablebody to cause the piston to move and, in turn, cause delivery of theprotein or peptide from the enclosure.
 8. The osmotic delivery systemaccording to claim 7, wherein the osmotic agent comprises an osmagent oran osmopolymer.
 9. The osmotic delivery system according to claim 7,wherein the osmotic agent comprises a semisolid or a solid.
 10. Theosmotic delivery system according to claim 7, wherein the osmotic agentis magnesium sulfate, magnesium chloride, potassium sulfate, sodiumchloride, sodium sulfate, lithium sulfate, sodium phosphate, potassiumphosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate,tartaric acid, raffinose, sucrose, glucose, lactose, fructose, dextran,poly(hydroxy-alkyl methacrylates) with molecular weight of about 30,000to about 5,000,000, poly(vinylpyrrolidone) with molecular weight ofabout 10,000 to about 360,000, anionic and cationic hydrogels,polyelectrolyte complexes, poly(vinyl alcohol) having low acetateresidual, optionally cross-linked with glyoxal, formaldehyde orglutaraldehyde and having a degree of polymerization of about 200 toabout 30,000, a mixture of methyl cellulose, cross-linked agar andcarboxymethylcellulose, a mixture of hydroxypropyl methylcellulose andsodium carboxymethylcellulose, a polymer of N-vinyllactams,polyoxyethylene-polyoxypropylene gels, a polyoxybutylene-polyethyleneblock copolymer gel, carob gum, polyacrylic gel, polyester gel, polyureagel, polyether gel, polyamide gel, polypeptide gel, polyamino acid gel,polycellulosic gel, carbopol acidic carboxy polymer having a molecularweight of about 250,000 to about 4,000,000, Cyanamer polyacrylamide,cross-linked indene-maleic anhydride polymer, polyacrylic acid having amolecular weight of about 80,000 to about 200,000, Polyox Polyethyleneoxide polymer having a molecular weight of about 100,000 to about5,000,000, starch graft copolymer, or an acrylate polymerpolysaccharide.
 11. The osmotic delivery system according to claim 7,wherein the osmotic agent is in the form of a tablet, pellet, or powder.12. The osmotic delivery system according to claim 7, wherein theprotein is interferon.
 13. The osmotic delivery system according toclaim 7, wherein the protein is omega interferon.
 14. The osmoticdelivery system according to claim 7, wherein the protein is leuprolide.15. The osmotic delivery system according to claim 7, wherein theenclosure includes an opening and the semipermeable body includes asemipermeable membrane, the semipermeable membrane located at leastpartially within the opening.
 16. The osmotic delivery system accordingto claim 7, wherein the recess is a concave indentation, square cavity,conical pit, gouge, or depression.
 17. The osmotic delivery systemaccording to claim 7, wherein the piston includes at least one rib foreffecting a movable seat with the enclosure.
 18. The osmotic deliverysystem according to claim 7, wherein the protein or peptide is locatedin the interior of the enclosure, the protein or peptide being deliveredfrom the enclosure when the piston moves.
 19. The osmotic deliverysystem according to claim 7, wherein the protein or peptide is locatedin the interior of the enclosure, the piston defining the movable sealthat separates the osmotic agent from the protein or peptide.